Abstract

Prostaglandin (PG) D2 is formed by two distinct prostaglandin D synthases (PGDS): lipocalin-type PGDS (L-PGDS), which acts as a PGD2 producing enzyme and as extracellular lipophilic transporter, and hematopoietic PGDS (H-PGDS), a sigma glutathione-S-transferase. PGD2 plays an important role in the maintenance of vascular function; however, the relative contribution of LPGDS and HPGDS dependent formation of PGD2 in this setting is unknown. To gain insight into the function played by these distinct PGDSs, we assessed systemic blood pressure (BP) and thrombogenesis in L-Pgds and H-Pgds KO mice. Deletion of L-Pgds depresses urinary PGD2 metabolite (PGDM) by ~35% while deletion of H-Pgds does so by ~90%. Deletion of L-Pgds, but not H-Pgds, elevates BP and accelerates the thrombogenic occlusive response to a photochemical injury to the carotid artery. HQL-79, an H-PGDS inhibitor, further depresses PGDM in L-Pgds KO mice, but has no effect on BP or on the thrombogenic response. Gene expression profiling reveals that pathways relevant to vascular function are dysregulated in the aorta of L-Pgds KOs. These results indicate that the functional impact of L-Pgds deletion on vascular homeostasis may result from an autocrine effect of L-PGDS dependent PGD2 on the vasculature and/or the L-PGDS function as lipophilic carrier protein.